Convenient and efficient synthesis of 1-oxo-1,2,3,4-tetrahydrocarbazoles via Fischer indole synthesis

Article abstract of DOI:10.1080/00397910802499567

A convenient synthesis of 1-oxo-1,2,3,4-tetra-hydrocarbazoles has been developed by reaction of 2-aminocyclohexanone hydrochlorides with various phenylhydrazine hydrochlorides via Fischer indole synthesis under mild conditions. The method is more satisfac

Full text of DOI:10.1080/00397910802499567

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Convenient and Efficient
Synthesis of 1-Oxo-1,2,3,4-
tetrahydrocarbazoles via
Fischer Indole Synthesis
Rong Sheng a , Li Shen a , You-Qin Chen a & Yong-
Zhou Hu a
a Zhejiang University–Ecole Normale Supeŕieure
(ZJU-ENS) Joint Laboratory of Medicinal Chemistry,
College of Pharmaceutical Sciences, Zhejiang
University, Hangzhou, China
Version of record first published: 25 Feb 2009.
To cite this article: Rong Sheng , Li Shen , You-Qin Chen & Yong-Zhou Hu (2009):
Convenient and Efficient Synthesis of 1-Oxo-1,2,3,4-tetrahydrocarbazoles via Fischer
Indole Synthesis, Synthetic Communications: An International Journal for Rapid
Communication of Synthetic Organic Chemistry, 39:6, 1120-1127
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Synthetic Communications1, 39: 1120–1127, 2009
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397910802499567
Convenient and Efficient Synthesis
of 1-Oxo-1,2,3,4-tetrahydrocarbazoles
via Fischer Indole Synthesis
Rong Sheng, Li Shen, You-Qin Chen, and Yong-Zhou Hu
´
Zhejiang University–Ecole Normale Superieure (ZJU-ENS) Joint
Laboratory of Medicinal Chemistry, College of Pharmaceutical Sciences,
Zhejiang University, Hangzhou, China
Abstract: A convenient synthesis of 1-oxo-1,2,3,4-tetra-hydrocarbazoles has been
developed by reaction of 2-aminocyclohexanone hydrochlorides with various
phenylhydrazine hydrochlorides via Fischer indole synthesis under mild condi-
tions. The method is more satisfactory in terms of the easy availability of starting
materials and the simple one-pot operation.
Keywords: 2-Aminocyclohexanone, Fischer indole synthesis, 1-oxo-1,2,3,4-tetra-
hydrocarbazole, phenylhydrazine
Although 1-oxo-1,2,3,4-tetrahydrocarbazoles rarely occur in nature, they
have been increasingly important intermediates in the synthesis of various
biologically active heterocyclic compounds because of their unique
structures, such as indo[2,3-a]carbazoles,[1] furo[2,3-a]-carbazoles,[2]
pyrimidino[4,5-a]-carbazoles,[3] pyrazolino[3,2,1-j,k]carbazoles,[4] thieno-
[2,3-a]carbazoles,[5] and so on. Many methods for the synthesis of
1-oxo-1,2,3,4-tetrahydrocarbazoles have already been developed. These
include, for example, cyclization of diphenylhydrazone of cyclohexane-
1,2-dione or 2-phenylhydrazono cyclohexanone via Fischer indole synth-
esis,[6–8] oxidation of 1,2,3,4-tetrahydro-9H-carbazole with SeO2 or
[9]
Received September 11, 2008.
Address correspondence to Yong-Zhou Hu, ZJU-ENS Joint Laboratory of
Medicinal Chemistry, College of Pharmaceutical Sciences, Zhejiang University,
Hangzhou 310058, China. E-mail: huyz@zju.edu.cn
1120

1-Oxo-1,2,3,4-tetrahydrocarbazoles
1121
Scheme 1. Synthesis of 1-oxo-1,2,3,4-tetrahydrocarbazoles.
I2O5,[10] cyclization of thiohydroxamates with camphorsulfonic acid,[11]
and cyclization of indole-3-butanic acid in refluxing xylene with P2O5,
polyphosphoric acid (PPA), or Lewis acid Bi(OTf)3.[12–14] Some of these
methods have modest yields, harsh reaction conditions, or tedious proce-
dures. As part of our growing interest in using phenylhydrazines as
heterocyclic building blocks in organic synthesis,[15–17] we describe herein
a convenient and efficient one-pot synthetic route for the preparation
of 1-oxo-1,2,3,4-tetrahydro-carbazoles via Fischer indole synthesis from
2-aminocyclohexanone hydrochlorides and various phenylhydrazine
hydrochlorides. The method is more satisfactory in terms of the easy
availability of starting materials and the simple one-pot operation, as
shown in Scheme 1.
RESULTS AND DISCUSSION
When an equimolar mixture of 2-aminocyclohexanone hydrochloride 1a
and phenylhydrazine hydrochloride 2a was refluxed in glacial acetic acid,
two products, 1-oxo-1,2,3,4-tetrahydrocarbazole 3a and indolo[2,3-a]
carbazole, were yielded in the ratio of 1:2. The reason was that 3a could
proceed in the second Fisher indole synthesis with 2a to give indolo[2,3-
a]carbazole. When the amount of 2a was enhanced to 4 equiv, a single pro-
duct (indolo[2,3-a]carbazole) could be obtained.[16] In opposition, when
increasing the amount of compound 1a, little effect on the yield of 1-
oxo-1,2,3,4-tetrahydrocarbazole was exhibited. To seek the general method
to get target compound 3a in high yield, various reaction conditions were
scrutinized (see Table 1), but no promising results could be observed.
The mechanism of this reaction probably involves a Fisher indole
synthesis, as already reported by our laboratory. (Scheme 2).[16] We
believed that the presence of the hydrochloric acid in two reagents would
be an important factor to speed up the 1-oxo-1,2,3,4-tetrahydrocarbazole
converting to indolo-[2,3-a]-carbazole. For that reason, condensation of
free 2-aminocyclohexanone with phenyl hydrazine in weak acid medium
would be beneficial to the reaction. Because the 2-aminocyclohexanone
and phenyl hydrazine are unstable in air, in this procedure, an equimolar

1122
R. Sheng et al.
Table 1. Acid catalysts screening
Entry
Acid catalyst
Reaction temp. (ꢀC) Mole ratioa Yieldb (%)
1
2
3
4
5
6
7
95% HOAc
80% HOAc
Toluene=33% HOAc
TsOH ꢁ H2O=EtOH
THF=33% HOAc
97% HCOOH
100
1:1
32
40
39
29
35
15
0c
reflux
reflux
reflux
reflux
reflux
r.t.
1.2:1
1.2:1
1.2:1
1:1
1:1
1:1
PCl3=CH2Cl2
aThe ratio of 2-aminocyclohexanone hydrochloride 1a and phenylhydrazine
hydrochloride 2a.
bIsolated yield.
cNo reaction had occurred.
of 2 N sodium hydroxide solution was added to the mixture of 1a and 2a
to produce 2-aminocyclohexanone and phenyl hydrazine in situ, followed
by refluxing in glacial acetic acid for 5 h. A yield of 55% of target com-
pound 3a was obtained. Encouraged by this result, we studied different
reaction parameters. The reaction was performed in different acidic
solvents such as HOAc, HCOOH, HOAc–H2O, HCOOH–H2O,
HOAc–MeOH, and so on. The results disclosed that 80% HOAc was a
suitable solvent for the reaction in terms of yield and reaction time. Next,
the optimization of the molar ratio of 1a to 2a was tested, and it was
Scheme 2. Plausible reaction mechanism for the synthesis of 1-oxo-1,2,3,4-
tetrahydrocarbazoles.

1-Oxo-1,2,3,4-tetrahydrocarbazoles
1123
found that the ratio of 1.2:1 was sufficient for this reaction with this,
the yield of the product 3a could be improved up to 73%, but the excess
1a beyond this ratio did not show further increase in conversion and in
yield. Having established the optimized reaction conditions, a series of
substituted 1-oxo-1,2,3,4-tetrahydrocarbazoles 3a–3s were synthesized
in good to excellent yields, the results are shown in Table 2. However,
reacting 1a with 3-chlorophenylhydrazine hydrochloride 2 m gave a
mixture of 5-chloro-1-oxo-1,2,3,4-tetrahydrocarbazoles 3 m and 7-chloro-
1-oxo-1,2,3,4-tetrahydrocarbazoles 3m0 in a 1.3:1 ratio (entry 13), which
could not be separated.
In summary, the present procedure provides an efficient method for
the synthesis of 1-oxo-1,2,3,4-tetrahydrocarbazoles via Fischer indole
synthesis. The advantages offered by this method are available starting
material, simple operation, insensitivity to air and moisture, high
yields of products, and cost-effectiveness. The selected products were
characterized by 1H NMR, 13C NMR, elemental analysis, and mass
spectroscopic (MS) data.
Table 2. Synthesis of 1-oxo-1,2,3,4-tetrahydrocarbazoles
Compound
R1
R2
Yielda (%)
M.p. (ꢀC)
3a
3b
3c
H
H
H
H
H
H
H
H
H
H
H
H
H
H
73
90
74
91
94
77
75
60
65
60
57
50
78b
83
70
77
77
45
55
166–168 (165–168)[10]
206–207 (210)[18]
212–214 (210)[18]
206–208 (212)[6]
223–225 (220)[18]
222–223 (230)[18]
239–240
156–158 (164)[18]
121–122 (108)[18]
132–134 (119)[6]
158–160 (159)[18]
164–165 (158)[18]
4-CH3
4-OCH3
4-F
3d
3e
4-Cl
3f
4-Br
4-SO2CH3
2-CH3
2-OCH3
2-F
2-Cl
2-Br
3-Cl
H
4-Cl
H
4-Cl
H
4-Cl
3g
3h
3i
3j
3k
3l
3 m, 3m0
3n
3o
3p
3q
3r
4-CH3
4-CH3
4-Ph
4-Ph
4-C(CH3)3
4-C(CH3)3
192–194 (193–195)[19]
181
167–168
187–189
177–179
260–262
3s
aIsolated yield.
bA 1.3:1 mixture of 3m and 3m0.

1124
R. Sheng et al.
EXPERIMENTAL
Melting points were obtained on a B-540 Buchi melting-point apparatus
and are uncorrected. 1H and 13C NMR spectra were recorded on a
Brucker AM 400-MHz spectrometer (at 400 and 100 MHz, respectively)
with SiMe4 as the internal standard in CDCl3 or dimethyl sulfoxide
(DMSO-d6). Element analysis were performed on an Eager 300 instru-
ment. Infrared (IR) spectra were recorded on a Brucker Vector-22
spectrophotometer.
General Procedure for the Preparation of 1-Oxo-1,2,3,4-
tetrahydrocarbazole (3a)
A solution of 2 N sodium hydroxide (0.48 mL, 0.98 mmol) was added
dropwise to the mixture of 2-aminocyclohaxanone hydrochloride
(79.3 mg, 0.53 mmol) and phenylhydrazine hydrochloride (63.6 mg, 0.44
mmol) and stirred for 15 min at room temperature. Then, the mixture
was refluxed for 5 h followed by addition of 80% HOAc solution (3
mL). After the reaction mixture was cooled to room temperature, it was
poured into a saturated NaHCO3 solution (10 mL) and extracted with
EtOAc (3 ꢁ 10 mL). The combined organic layers were dried over anhy-
drous Na2SO4 and concentrated in vacuo. The crude product was purified
by a silica-gel column chromatography with petroleum ether and EtOAc
(5:1) as eluent to give the desired 1-oxo-1,2,3,4-tetrahydrocarbazole (3a).
Previously reported materials were characterized by comparison of
1
their mp, IR, H NMR, and MS data with those of authentic samples.
All new compounds gave satisfactory spectral data in accordance with
their proposed structures.
Data for Selected Compounds
Compound 3g
IR (KBr, cmꢂ1): 3212, 3028, 2939, 1652, 1566, 1298, 1138, 772; 1H NMR
(400 MHz, DMSO-d6): d 2.17 (m, 2H, CH2), 2.60 (m, 2H, CH2), 3.02
(m, 2H, CH2), 3.20 (s, 3H, CH3), 7.58 (d, J ¼ 8.8 Hz, 1H, ArH), 7.79
(dd, J ¼ 8.8 Hz, 1H, ArH), 8.32 (s, 1H, ArH), 12.19 (s, 1H, NH); 13C
NMR (100 M, DMSO-d6): 21.0, 24.8, 38.4, 44.6, 114.0, 122.4, 124.1,
124.9, 129.6, 132.5, 133.5, 140.0, 191.2; MS (ESI): m=z ¼ 263 [Mþ]; Anal.
calcd. for C13H13NO3S: C, 59.30, H; 4.98; N, 5.32. Found: C, 59.77;
H, 4.69; N, 5.59.

1-Oxo-1,2,3,4-tetrahydrocarbazoles
1125
Compound 3o
IR (KBr, cmꢂ1): 3252, 2957, 2872, 1647, 1541, 1457, 1259, 808; 1H NMR
(400 MHz, DMSO-d6): d 1.12 (d, J ¼ 6.4 Hz, 3H, CH3), 2.36 (m, 2H,
CH2), 2.47 (m, 2H, CH2), 3.02 (dd, J ¼ 16.0, 3.2 Hz, 1H, CH), 7.28 (d,
J ¼ 8.8 Hz, 1H, ArH), 7.41 (d, J ¼ 8.8 Hz, 1H, ArH), 7.71 (s, 1H, ArH),
11.82 (s, 1H, NH); 13C NMR (100 MHz, DMSO-d6): 21.4, 29.2, 32.8,
46.6, 114.8, 120.6, 124.6, 126.5, 126.5, 127.1, 132.5, 136.9, 190.7; MS
(ESI): m=z ¼ 235 [M þ 2], 233 [Mþ]; (Anal. calcd. for C13H12ClNO:
C, 66.81, H: 5.18; N, 5.99. Found: C, 66.77; H, 5.39; N, 5.78.
Compound 3p
1
IR (KBr, cmꢂ1): 3253, 3060, 2922, 1647, 1538, 1455, 747, 702; H NMR
(400 MHz, DMSO-d6): d 2.63 (dd, J ¼ 16.4, 3.2 Hz, 1H, CH2), 2.99 (m,
2H, CH2), 3.25 (dd, J ¼ 16.0, 4.4 Hz, 1H, CH2), 3.56 (m, 1H, CH), 7.06
(t, J ¼ 7.6 Hz, 1H, ArH), 7.24 (t, J ¼ 7.6 Hz, 1H, ArH), 7.30 (m, 3H,
ArH), 7.42 (m, 3H, ArH), 7.67 (d, J ¼ 8.0 Hz, 1H, ArH), 11.74 (s, 1H,
NH); 13C NMR (100 MHz, DMSO-d6): d 29.3, 43.3, 45.4, 113.2, 120.1,
121.6, 125.5, 126.7, 127.0, 127.4, 127.5, 128.8, 131.4, 138.7, 144.5,
189.7; MS (ESI): m=z ¼ 261 [Mþ]; Anal. Calcd. for C18H15NO: C,
82.73; H, 5.79; N, 5.36. Found: C, 83.04; H, 5.52; N, 5.08.
Compound 3q
1
IR (KBr, cmꢂ1): 3252, 3027, 2919, 1645, 1540, 1467, 809, 729, 698; H
NMR (400 MHz, DMSO-d6): d 2.64 (d, J ¼ 16.0 Hz, 1H, CH2), 3.01
(m, 2H, CH2), 3.27 (d, J ¼ 16.0 Hz, 1H, CH2), 3.60 (t, J ¼ 12.0 Hz, 1H,
CH), 7.24 (t, J ¼ 8.0 Hz, 1H, ArH), 7.30 (m, 3H, ArH), 7.41 (t, J ¼ 7.2 Hz,
Hz, 3H, ArH), 7.79 (s, 1H, ArH), 11.90 (s, 1H, NH); 13C NMR (100
MHz, DMSO-d6): 29.1, 43.0, 45.3, 114.9, 120.8, 124.7, 126.4, 126.7,
126.9, 127.0, 127.4, 128.8, 132.5, 137.0, 144.4, 190.0; MS (ESI): m=z ¼ 297
[M þ 2], 295 [Mþ]; Anal. calcd. for C18H14ClNO: C, 73.10; H, 4.77; N,
4.74. Found: C, 73.06; H, 4.55; N, 4.68.
Compound 3r
IR (KBr, cmꢂ1): 3262, 3078, 2957, 2851, 1643, 1543, 1476, 760; 1H NMR
(400 MHz, DMSO-d6): d 1.00 (s, 9H, CH3), 2.02 (m, 1H, CH2), 2.38 (m,
2H, CH2), 2.61 (m, 1H, CH2), 3.11 (dd, J ¼ 16.0, 3.6 Hz, 1H, CH), 7.06 (t,
J ¼ 7.6 Hz, 1H, ArH), 7.28 (t, J ¼ 7.6 Hz, 1H, ArH), 7.38 (d, J ¼ 8.0 Hz,
1H, ArH), 7.70 (d, J ¼ 8.0 Hz, 1H, ArH), 11.59 (s, 1H, NH); 13C NMR

1126
R. Sheng et al.
(100 MHz, DMSO-d6): 28.4, 29.3, 32.1, 40.5, 47.9, 112.6, 118.9, 120.7, 122.8,
123.2, 129.6, 134.1, 137.5, 190.1; MS (EI): m=z ¼ 241 [Mþ]; Anal. calcd. for
C16H19NO: C, 79.63; H, 7.94; N, 5.80. Found: C, 79.73; H, 7.62; N, 5.98.
Compound 3s
1
IR (KBr, cmꢂ1): 3249, 2962, 2868, 1643, 1542, 1468, 801; H NMR (400
MHz, DMSO-d6): d 0.99 (s, 9H, CH3), 2.01 (t, J ¼ 12.0 Hz, 1H, CH2),
2.47 (m, 3H, CH2), 3.13 (dd, J ¼ 16.0, 2.0 Hz, 1H, CH), 7.28 (d,
J ¼ 9.2 Hz, 1H, ArH), 7.39 (d, J ¼ 9.2 Hz, 1H, ArH), 7.82 (s, 1H, ArH),
11.80 (s, 1H, NH); 13C NMR (100 MHz, DMSO-d6): 28.2, 29.6, 32.2,
40.3, 47.8, 114.2, 121.0, 124.8, 125.9, 126.7, 127.6, 132.4, 137.2, 190.4;
MS (ESI): m=z ¼ 277 [M þ 2], 275 [Mþ]; Anal. calcd. for C16H18ClNO:
C, 69.69; H, 6.58; N, 5.08. Found: C, 69.94; H, 6.35; N, 5.38.
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